We seek to followup on the findings that acetycholine (ACH) supersensitivity (a) may be a genetic vulnerability factor of familial depression (b) increases the risk of coexisting Panic - and apply the biological high-risk genetic study method to investigate the pathophysiological relationship of panic to Major Depressive disorders (MDD). This issue has important clinical and research implications and is a subject of intense controversy. Three groups of age and sex matched, first-degree relatives (groups A-C) and an additional fourth group (D) of patients will be tested on the speed of rapid-eye-movement (REM) sleep-induction following arecoline challenge, an index of cholinergic sensitivity. The relative groups (N=20 each) are: (A) Panic without MDD (B) MDD with out Panic (C) normal. The key to the genetic method is the selection of relatives (groups A-C) only from pedigrees with both the ACH(+) risk factor and MDD + Panic disorders present in a proband. The fourth group (D) consists of Panic patients without personal or family history of MDD. (N=20). Groups A-D will be tested drug free and in remission. The proposal addresses two key questions: are Panic and MDD co-aggregating within pedigrees, phenotypic expressions of the same shared diathesis? An affirmative answer would identify an important subgroups of panic patients with an inherited ACH pathophysiology, similar to MDD. Can they be distinguished from other Panic patients without familial loading of MDD?. This will help define a meaningful source of heterogeneity within the domain of Panic disorders, and may lead to more biologically specific, diagnostic, treatment and prognostic strategies